During the process of open mitosis in higher eukaryotic cells, the nuclear envelope (NE) is disassembled and reassembled with highly organized and periodical dynamic morphological changes. Recent studies demonstrated that LEM-domain protein family mediates interactions among inner nuclear membrane, nuclear lamina protein and chromatin by interacting with barrier-to-autointegration-factor (BAF). The structure and function of the ternary complex formed by LEM-domain protein, nuclear lamina protein and BAF are dependent on each other. Moreover, the network formation based on this structure and function is critical for the development of basic biological processes of nuclear, and it plays important roles in chromatin separation in late metaphase and anaphase, NE reassembly after mitosis, morphological maintenance of nuclear and NE in interphase, regulation of DNA replication and DNA damage repair, regulation of gene expression and signaling pathway, and infection of retrovirus. Mutations in genes encoding LEM family proteins have important impacts on development and progression of laminopathic diseases and tumorigenesis. This review provides a detailed summary of structural and functional studies of the LEM family proteins.
[1] Schirmer EC, Florens L, Guan TL, Yates JRⅢ, Gerace L. Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science , 2003, 301(5638): 1380-1382.
[2] Wilkie GS, Korfali N, Swanson SK, Malik P, Srsen V, Batrakou DG, de lasHeras J, Zuleger N, Kerr ARW, Florens L, Schirmer EC. Several novel nuclear envelope transmembrane proteins identified in skeletal muscle have cytoskeletal associations. Mol Cell Proteomics , 2011, 10(1): M110.003129.
[3] Korfali N, Wilkie GS, Swanson SK, Srsen V, Batrakou DG, Fairley EA, Malik P, Zuleger N, Goncharevich A, de Las Heras J, Kelly DA, Kerr ARW, Florens L, Schirmer EC. The leukocyte nuclear envelope proteome varies with cell activation and contains novel transmembrane proteins that affect genome architecture. Mol Cell Proteomics , 2010, 9(12): 2571-2585.
[4] Lin F, Blake DL, Callebaut I, Skerjanc IS, Holmer L, McBurney MW, Paulin-Levasseur M, Worman HJ. MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J Biol Chem , 2000, 275(7): 4840-4847.
[5] Cai ML, Huang Y, Ghirlando R, Wilson KL, Craigie R, Clore GM. Solution structure of the constant region of nuclear envelope protein LAP2 reveals two LEM-domain structures: one binds BAF and the other binds DNA. EMBO J , 2001, 20(16): 4399-4407.
[6] Shumaker DK, Lee KK, Tanhehco YC, Craigie R, Wilson KL. LAP2 binds to BAF?DNA complexes: requirement for the LEM domain and modulation by variable regions. EMBO J , 2001, 20(7): 1754-1764.
[7] Cai ML, Huang Y, Suh JY, Louis JM, Ghirlando R, Craigie R, Clore GM. Solution NMR structure of the barrier- to-autointegration factor-emerin complex. J Biol Chem , 2007, 282(19): 14525-14535.
[8] Brachner A, Braun J, Ghodgaonkar M, Castor D, Zlopasa L, Ehrlich V, Jiricny J, Gotzmann J, Knasmüller S, Foisner R. The endonuclease Ankle1 requires its LEM and GIY-YIG motifs for DNA cleavage in vivo. J Cell Sci , 2012, 125(Pt 4): 1048-1057.
[9] Asencio C, Davidson IF, Santarella-Mellwig R, Ly-Hartig TB, Mall M, Wallenfang MR, Mattaj IW, Gorjanacz M. Coordination of kinase and phosphatase activities by Lem4 enables nuclear envelope reassembly during mitosis. Cell , 2012, 150(1): 122-135.
[10] Zheng RL, Ghirlando R, Lee MS, Mizuuchi K, Krause M, Craigie R. Barrier-to-autointegration factor (BAF) bridges DNA in a discrete, higher-order nucleoprotein complex. Proc Natl Acad Sci USA , 2000, 97(16): 8997-9002.
[11] Mansharamani M, Wilson KL. Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-to-autointegration factor. J Biol Chem , 2005, 280(14): 13863-13870.
[12] Simon DN, Wilson KL. The nucleoskeleton as a genome-associated dynamic 'network of networks'. Nat Rev Mol Cell Biol , 2011, 12(11): 695-708.
[13] Liu J, Lee KK, Segura-Totten M, Neufeld E, Wilson KL, Gruenbaum Y. MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. Proc Natl Acad Sci USA , 2003, 100(8): 4598-4603.
[14] Hirano Y, Segawa M, Ouchi FS, Yamakawa Y, Furukawa K, Takeyasu K, Horigome T. Dissociation of emerin from barrier-to-autointegration factor is regulated through mitotic phosphorylation of emerin in a xenopus egg cell-free system. J Biol Chem , 2005, 280(48): 39925-39933.
[15] Burke B, Stewart CL. The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol , 2013, 14(1): 13-24.
[16] Berk JM, Tifft KE, Wilson KL. The nuclear envelope LEM-domain protein emerin. Nucleus-Austin , 2013, 4(4): 298-314.
[17] Gant TM, Harris CA, Wilson KL. Roles of LAP2 proteins in nuclear assembly and DNA replication: Truncated LAP2β proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopuslaevis extracts. J Cell Biol , 1999, 144(6): 1083-1096.
[18] Furukawa K, Fritze CE, Gerace L. The major nuclear envelope t
